Methods of use for 2,5-dihydroxybenzene sulfonic acid compounds for the treatment of cancer, rosacea and psoriasis

ABSTRACT

The invention describes compositions and methods of use for 2,5-dihydroxybenzene sulfonic acid compounds and pharmaceutically acceptable salts thereof. The invention provides methods for (a) treating skin cancer; (b) treating cancer of the organs; (c) treating leukemia; (d) improving the efficacy of chemotherapy, radiation therapy and/or cancer immunotherapy; (e) treating rosacea; and (f) treating psoriasis by administration of a composition comprising at least one 2,5-dihydroxybenzene sulfonic acid compound or a pharmaceutically acceptable salt thereof, and, optionally at least one therapeutic agent. Also disclosed are compositions comprising administration of at least one 2,5-dihydroxybenzene sulfonic acid compound, or a pharmaceutically acceptable salt thereof, and, at least one therapeutic agent. In the invention the 2,5-dihydroxybenzene sulfonic acid compounds or pharmaceutically acceptable salts thereof are 2,5-dihydroxybenzene sulfonic acid, calcium 2,5-dihydroxybenzenesulfonate, potassium 2,5-dihydroxybenzenesulfonate, magnesium 2,5-dihydroxybenzenesulfonate and diethylamine 2,5-dihydroxybenzenesulfonate.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 11/506,469, filed Aug. 16, 2006, which is a continuation-in-partapplication of U.S. application Ser. No. 10/588,166, which is the 35U.S.C. §371 National Stage application of International Application No.PCT/ES05/70017, filed Feb. 16, 2005, which claims the benefit ofpriority of Spanish Application No. P200400371, filed Feb. 17, 2004. Theforegoing applications are incorporated by reference herein in theirentirety.

FIELD OF THE INVENTION

The invention describes compositions and methods of use for2,5-dihydroxybenzene sulfonic acid compounds and pharmaceuticallyacceptable salts thereof. The invention provides methods for (a)treating skin cancer; (b) treating cancer of the organs; (c) treatingleukemia; (d) improving the efficacy of chemotherapy, radiation therapyand/or cancer immunotherapy; (e) treating rosacea; and (f) treatingpsoriasis by administration of a composition comprising at least one2,5-dihydroxybenzene sulfonic acid compound or a pharmaceuticallyacceptable salt thereof, and, optionally at least one therapeutic agent.Also disclosed are compositions comprising administration of at leastone 2,5-dihydroxybenzene sulfonic acid compound, or a pharmaceuticallyacceptable salt thereof, and, at least one therapeutic agent. In theinvention the 2,5-dihydroxybenzene sulfonic acid compounds orpharmaceutically acceptable salts thereof are 2,5-dihydroxybenzenesulfonic acid, calcium 2,5-dihydroxybenzenesulfonate, potassium2,5-dihydroxybenzenesulfonate, magnesium 2,5-dihydroxybenzenesulfonateand diethylamine 2,5-dihydroxybenzenesulfonate.

BACKGROUND OF THE INVENTION

Despite recent advances in chemotherapy and radiation, cancer is one ofthe leading causes of death at any age in the United States. There arenearly three million new cancer cases diagnosed every year. The overallfive-year survival approximates fifty percent for all patients, and theprognosis remains particularly poor for those with advanced solidtumors.

Rosacea is a common facial and eye disease that currently affectsmillions worldwide. It is a chronic and progressive cutaneous vasculardisorder, primarily involving the malar and nasal areas of the face.Rosacea is characterized by flushing, erythema, papules, pustules,telanglectasia, facial edema, ocular lesions, and, in its most advancedand severe form, hyperplasia of tissue and sebaceous glands leading torhinophyma. Rhinophyma, a florid overgrowth of the tip of the nose withhypervascularity and modularity, is an unusual progression of rosacea ofunknown cause. Ocular lesions are common, including mild conjunctivitis,burning, and grittiness. Blepharitis, the most common ocularmanifestation, is a nonulcerative condition of the lid margins.

Psoriasis is a chronic disease that affects about 2-3% of the worldpopulation. It is characterized by hyperproliferation of epidermalcells. The symptoms of psoriasis include sharply defined erythematouspatches covered with a distinctive scale, hyperproliferation of theepidermis, incomplete differentiation of keratinocytes and dermalinflammation. Clinical variants of psoriasis include erythroderma,seborrheic, inverse, guttate, and photosensitive psoriasis, pustularvariants and Reiter's disease. Currently there is no cure for psoriasis

There is still a need in the art for new effective therapies to treatcancer, to treat rosacea and to treat psoriasis. The invention isdirected to these, as well as other, important ends.

SUMMARY OF THE INVENTION

The invention describes methods for (a) treating skin cancer; (b)treating cancer of an organ; (c) treating leukemia; and (d) improvingthe efficacy of chemotherapy, radiation therapy and/or cancerimmunotherapy in a patient in need thereof comprising administering tothe patient an effective amount of at least one 2,5-dihydroxybenzenesulfonic acid compound or a pharmaceutically acceptable salt thereof.The methods can optionally further comprise the administration of atleast one therapeutic agent, such as, for example, chemotherapeuticagents, steroids, retinoids, antimicrobial compounds, antioxidants,anti-inflammatory compounds, NMDA receptor antagonists, endothelinantagonists, immunomodulating agents, vitamin D analogues, salicylicacid, and combinations of two or more thereof. In this embodiment of theinvention, the methods can involve (i) administering the2,5-dihydroxybenzene sulfonic acid compound, or (ii) administering the2,5-dihydroxybenzene sulfonic acid compound and at least one therapeuticagent. The 2,5-dihydroxybenzene sulfonic acid compounds and/ortherapeutic agents can be administered separately or as components ofthe same composition in one or more pharmaceutically acceptablecarriers.

The invention describes methods for treating rosaeca in a patient inneed thereof comprising topically administering to the patient aneffective amount of at least one 2,5-dihydroxybenzene sulfonic acidcompound or a pharmaceutically acceptable salt thereof. The methods canoptionally further comprise the administration of at least onetherapeutic agent, such as, for example, chemotherapeutic agents,steroids, retinoids, antimicrobial compounds, antioxidants,anti-inflammatory compounds, NMDA receptor antagonists, endothelinantagonists, immunomodulating agents, vitamin D analogues, salicylicacid, and combinations of two or more thereof. In this embodiment of theinvention, the methods can involve (i) topically administering the2,5-dihydroxybenzene sulfonic acid compound, or (ii) topicallyadministering the 2,5-dihydroxybenzene sulfonic acid compound and atleast one therapeutic agent. The 2,5-dihydroxybenzene sulfonic acidand/or therapeutic agents can be administered separately or ascomponents of the same composition in one or more pharmaceuticallyacceptable carriers.

The invention describes methods for treating psoriasis in a patient inneed thereof comprising topically administering to the patient aneffective amount of at least one 2,5-dihydroxybenzene sulfonic acidcompound or a pharmaceutically acceptable salt thereof. The methods canoptionally further comprise the administration of at least onetherapeutic agent, such as, for example, chemotherapeutic agents,steroids, retinoids, antimicrobial compounds, antioxidants,anti-inflammatory compounds, NMDA receptor antagonists, endothelinantagonists, immunomodulating agents, vitamin D analogues, salicylicacid, and combinations of two or more thereof. In this embodiment of theinvention, the methods can involve (i) topically administering the2,5-dihydroxybenzene sulfonic acid compound, or (ii) topicallyadministering the 2,5-dihydroxybenzene sulfonic acid compound and atleast one therapeutic agent. The 2,5-dihydroxybenzene sulfonic acidand/or therapeutic agents can be administered separately or ascomponents of the same composition in one or more pharmaceuticallyacceptable carriers.

The invention provides compositions comprising at least one2,5-dihydroxybenzene sulfonic acid compound and at least one therapeuticagent, including, but not limited to, chemotherapeutic agents, steroids,retinoids, antimicrobial compounds, antioxidants, anti-inflammatorycompounds, NMDA receptor antagonists, endothelin antagonists,immunomodulating agents, vitamin D analogues, salicylic acid, andcombinations of two or more thereof. The invention also provides forsuch compositions in a pharmaceutically acceptable carrier.

These and other aspects of the present invention are explained in detailherein.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 shows histograms that demonstrate the potentiating effect ofchemotherapy (assessed as an antiproliferative effect) by2,5-dihydroxybenzene sulfonic acid, with different cytostatic compounds,(Panel A), Cisplatin (5 μg/ml); (Panel B), Vincristine (0.1 μl/ml);(Panel C), Paclitaxel (5 Ug/ml) and (Panel D), 5-fluorouracil (100μg/ml). Ordinates: Absorbance 595 nm; Abscises: white histogram(control); dotted (cytostatic compound; day 1); lined histogram(2,5-dihydroxybenzene sulfonic acid+cytostatic compound; day 1); squarehistogram (2,5-dihydroxybenzene sulfonic acid (day 0)+cytostaticcompound; day 1).

FIG. 2 shows the effect of the treatment with 2,5-dihydroxybenzenesulfonate (DHBS; 100 μM) on the proliferation of C6 rat glioma cells forthe cytostatic agents, cisplatin (CSP; 5 μg/ml) (Panel A), vincristine(VC; 0.5 μg/ml) (Panel B), paclitaxel (PTX; 5 μg/ml) (Panel C),5-fluorouracil (5FU; 100 μg/ml) (Panel D) and irinotecan (CPT; 0.1μg/ml) (Panel E). DHBS was either administered or not administered afterseeding the C6 cells (10⁴ per well) until fixation of the cells at 96 h.The cells were treated with the cytostatic agents for the last 48 h. They axes gives the absorbance at 595 nm. Data are expressed as mean±SEM ofthe absorbance at 595 nm that is proportional to the number of cellsstained with crystal violet from 3 experiments for each cytostaticagent. Open bars represent control cells; stripped bars represent cellstreated with the respective cytostatic agent and solid bars representcells treated with the combination of DHBS and each one of thecytostatic agent. In all cases, p<0.001 group treated with cytostaticagent alone vs group treated with DHBS plus the cytostatic agent.

FIG. 3 upper panels A, B and C, are the magnetic resonance images (MRIs)of rat brains showing the presence of tumours (indicated by the arrows)two weeks after the implantation of 10⁶ glioma cells. MRIs were obtainedbefore the treatment with irinotecan in two four-days cycles separatedby a four-days resting period (Panel A), before the treatment with2,5-dihydroxybenzene sulfonate (DHBS) (Panel B) or before the treatmentwith the combination of irinotecan plus 2,5-dihydroxybenzene sulfonate(Panel C). The lower panels D, E and F are the MRIs from rat brainsshowing the progression of the tumours (indicated by arrows) 6 weeksafter the implantation of C6 glioma cells. Panel D shows the MRIs aftertreatment with irinotecan (CPT-11; 10 mg/kg/day; i.p.); Panel E showsthe MRIs after treatment with 2,5-dihydroxybenzene sulfonate (200mg/kg/day; i.p.); (Panel F shows the MRIs after treatment with thecombination of irinotecan (CPT-11; 10 mg/kg/day; i.p.) plus2,5-dihydroxybenzene sulfonate (200 mg/kg/day; i.p.). Treatments werestarted 4 weeks after implantation.

FIG. 4 is a photograph showing the difference in size between twoheterotopic gliomas developed after subcutaneous implantation of 5×10⁵C6 glioma cells in a saline-treated rat (a) and in a rat treated withintra-tumoural injection of 2,5-dihydroxybenzene sulfonate (100 mg/kg)(b). Tumours were removed 10 days after treatment, which was done oneweek after implantation of tumour cells.

FIG. 5 shows the effects of intraperitoneal administration of2,5-dihydroxybenzene sulfonate (DHBS; 100 mg/kg; twice a day for 10days) or saline on the progression of established rat subcutaneousgliomas. Data are expressed as mean±SEM of tumor volume in mm³ from 6rats per group. *p<0.05 vs saline by unpaired t-test.

FIG. 6 are photographs showing the effects of 2,5-dihydroxybenzenesulfonate on melanoma growth. Panel A shows the melanoma in rabbitcornea in an untreated animal. Panel B depicts the histological featureof the melanoma obtained from the boxed area in Panel A. The strongtumor angiogenesis are indicated by asterisks in Panel B. Panel C showsthe reduced melanoma growth in an animal treated with2,5-dihydroxybenzene sulfonate (200 mg/ml; 0.5 ml/h for 14 days). PanelC depicts the histological feature from the boxed area in panel C.Scarce tumor cells (marked by arrows) and absence of angiogenesis wasobserved.

FIG. 7 shows photographs of a patient with infiltrative BCC: Panel Abefore treatment; Panels B and C at 2 and 4 weeks, respectively, aftertopical treatment with 2,5-dihydroxybenzene sulfonate cream (2.5%) twicea day; Panel D shows the patient 6 weeks after finishing treatment.

FIG. 8 shows the photograph of the same patient as in FIG. 7 two yearsafter completion of the treatment with 2,5-dihydroxybenzene sulfonatecream (2.5%).

FIG. 9 shows the histopathological pictures after 4 weeks of treatmentwith 2,5-dihydroxybenzene sulfonate cream (2.5%). Panel A shows there isno evidence of BCC in section specimen (Masson's trichrome staining;original magnification×22). Panel B is the same specimen as shown inPanel A), shows the presence of apoptotic cells that were revealed bythe terminal 2′-deoxyuridine-5′-triphosphate (dUTP) nick-end-labelling(TUNEL) positive cells with brown nuclei (stained by the TUNELtechnique; original magnification×65).

FIG. 10 shows photographs of a patient with infiltrative BCC: Panel Abefore treatment; Panel B after two months of topical treatment with2,5-dihydroxybenzene sulfonate cream (2.5%) twice a day; Panel C sixmonths after completion of the topical treatment with2,5-dihydroxybenzene sulfonate cream (2.5%) twice a day.

FIG. 11 shows photographs of a patient with nodular BCC: Panel A beforetreatment; Panel B after two months of topical treatment with2,5-dihydroxybenzene sulfonate cream (2.5%) twice a day; Panels B and Ctwo different times during the topical treatment with2,5-dihydroxybenzene sulfonate cream (2.5%) twice a day; Panel D aftersix months of topical treatment with 2,5-dihydroxybenzene sulfonatecream (2.5%) twice a day.

FIG. 12 shows the immunohistochemical detection of the cellproliferation rate in dermal tissue of skin specimens from 5 differentpatients with basal cell carcinoma before treatment (Panels a, b, c, d,e, respectively) and in specimens from the same patients after topicaltreatment with 2,5-dihydroxybenzene sulfonate cream (2.5%) twice a dayfor two months (Panels f, g, h, i, j, respectively). Immunostaining withchromogen diaminobenzidine (DAB) revealed the presence of Ki-67, amarker for cell proliferation.

FIG. 13 shows the immunohistochemical detection of the cellproliferation rate in epidermal tissue of skin specimens from 5different patients with basal cell carcinoma before treatment (Panels a,b, c, d, e, respectively) and in specimens from the same patients aftertopical treatment with 2,5-dihydroxybenzene sulfonate cream (2.5%) twicea day for two months (Panels f, g, h, i, j, respectively).Immunostaining with chromogen diaminobenzidine (DAB) revealed thepresence of Ki-67, a marker for cell proliferation.

FIG. 14 shows the immunohistochemical detection of vascularization indermal tissue of skin specimens from 5 different patients with basalcell carcinoma before treatment (Panels a, b, c, d, e, respectively) andin specimens from the same patients after topical treatment with2,5-dihydroxybenzene sulphonate cream (2.5%) twice a day for two months(Panels f, g, h, i, j, respectively). Immunostaining with chromogendiaminobenzidine (DAB) revealed the presence of CD34, a marker forvascularization.

FIG. 15 shows the histological detection of apoptosis rate in dermaltissue of skin specimens from 5 different patients with basal cellcarcinoma before treatment (Panels a, b, c, d, e, respectively) and inspecimens from the same patients after topical treatment with2,5-dihydroxybenzene sulphonate cream (2.5%) twice a day for two months(Panels f, g, h, i, j, respectively). The presence of apoptotic cellswas revealed by the terminal 2′-deoxyuridine-5′-triphosphate (dUTP)nick-end-labelling (TUNEL) method.

FIG. 16 shows the photograph of a patient with rosacea: Panel A beforetreatment; Panel B after two months of topical treatment with2,5-dihydroxybenzene sulfonate cream (2.5%) twice a day; Panel C oneyear post-treatment (C).

FIG. 17 shows the photograph of a patient with rosacea: Panel A beforetreatment; Panel B after three weeks of topical treatment with2,5-dihydroxybenzene sulfonate cream (2.5%) twice a day.

FIG. 18 shows the images of a hiperkeratosic psoriatic plaque located inthe rear region of the left elbow of a patient. Image A shows thepsoriatic plaque before treatment (day 0). Image B is the same plaqueafter six days of treatment with a cream that contains 5% of thepotassium salt of the 2,5-dihydroxybenzene sulfonic acid. Image C showsthe psoriatic plaque after 18 days of treatment with a cream thatcontains 5% of the potassium salt of the 2,5-dihydroxybenzene sulfonicacid.

DETAILED DESCRIPTION OF THE INVENTION

As used throughout the disclosure, the following terms, unless otherwiseindicated, shall be understood to have the following meanings.

“Patient” refers to animals, preferably mammals, most preferably humans,and includes males and females, and children and adults.

“Effective amount” refers to the amount of the compound and/orcomposition that is effective to achieve its intended purpose.

“Treating,” “treat” or “treatment” refers to using the compounds orcompositions of the present invention either prophylactically to preventthe symptoms of the disease or disorder, or therapeutically toameliorate an existing condition.

“Cancer” refers to a disease or disorder characterized by theuncontrolled division of cells and the ability of those cells to invadeother tissues, either by direct growth into adjacent tissue throughinvasion or by implantation into distant sites by metastasis.

“Skin cancer” refers to and includes, basal cell cacinoma, squamous cellcarcinoma, melanomas, keratoacanthoma, actinic keratosis, Bowen'sdisease, verrucae, sarcomas, angiosarcoma such as Kaposi's angiosarcomaand the like.

“Cancer of an organ” refers to and includes, breast cancer, bladdercancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer,lung cancer, cervical cancer, pancreatic cancer, prostate cancer, sweatgland cancinoma, sebaceous gland carcinoma, testicular cancer, thyroidcancer, ovarian cancer, Wilm's tumor, glioma, glioblastoma, meningioma,and the like.

“Leukemia” refers to and includes, blood borne cancers, such as, forexample, acute lymphocytic leukemia; acute myelocytic leukemia, such as,myeloblastic, promyeloblastic, myelomonocytic, erythrocytic leukemia,and the like; chronic leukemia, such as, chronic myelocytic(granulocytic) leukemia, chronic lymphocytic leukemia, and the like;polycytemia vera, lymphoma (Hodgkin's disease and non-Hodgkin'sdisease), multiple myeloma, Waldenström's macroglobulinemia, heavy chaindisease, and the like.

“Chemotherapy” refers to the use of a chemotherapeutic agent to treat acancer.

“Radiation therapy” or “radiotherapy” refers to the medical use ofionization radiation as part of the treatment of cancer to controlmalignant cells.

“Cancer immunotherapy” refers to the stimulation of the immune system toreject or destroy tumors, and, includes, but is not limited to, BCGimmunotherapy, topical immunotherapy, injection immunotherapy, and thelike.

“Psoriasis” refers to and includes, immune-mediated diseases whichaffects the skin and joints. When it affects the skin it commonlyappears as red scaly elevated patches called plaques. Psoriasis plaquesare areas of inflammation and excessive skin cell production.

“Therapeutic agent” includes any therapeutic agent that can be used totreat or prevent the diseases described herein. “Therapeutic agents”include, but are not limited to, chemotherapeutic agents, steroids,retinoids, antimicrobial compounds, antioxidants, anti-inflammatorycompounds, NMDA receptor antagonists, endothelin antagonists,immunomodulating agents, vitamin D analogues, salicylic acid, and thelike. Therapeutic agent includes the pharmaceutically acceptable saltsthereof, pro-drugs, and pharmaceutical derivatives thereof

“Lower alkyl” refers to branched or straight chain acyclic alkyl groupcomprising one to about four carbon atoms. Exemplary lower alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, and the like.

“Antimicrobial compound” refers to any compound that alters the growthof bacteria, fungi or virus whereby growth is prevented, modified,impaired, stabilized, inhibited or terminated. Antimicrobial compoundscan be microbiocidal or microbiostatic and include, but are not limitedto antibiotics, semisynthetic antibiotics, synthetic antibiotics,antifungal compounds, antiviral compounds, and the like.

“Antifungal compound” refers to any compound that alters the growth offungi whereby growth is prevented, modified, impaired, stabilized,inhibited or terminated.

“Antiviral compound” refers to any compound that alters the growth ofviral cells whereby growth is prevented, modified, impaired, stabilized,inhibited or terminated.

“Antioxidant” refers to and includes any compound that can react andquench a free radical including, but not limited to, free radicalscavengers, iron chelators, small-molecule antioxidants and antioxidantenzymes, and the like.

“Taxane” refers to any compound that contains the carbon core frameworkrepresented by formula A:

“NSAID” refers to a nonsteroidal anti-inflammatory compound or anonsteroidal anti-inflammatory drug. NSAIDs inhibit cyclooxygenase, theenzyme responsible for the biosyntheses of the prostaglandins andcertain autocoid inhibitors, including inhibitors of the variousisozymes of cyclooxygenase (including but not limited tocyclooxygenase-1 and -2), and as inhibitors of both cyclooxygenase andlipoxygenase.

“Organic cation” refers to a positively charged organic ion. Exemplaryorganic cations include alkyl substituted or unsubstituted ammoniumcations, primary, secondary and tertiary amines, alkyl amines, arylamines, cyclic amines, N,N′-dibenzylethylenediamine, and the like

“Inorganic cation” refers to a positively charged metal ion. Exemplaryinorganic cations include Group I metal cations, such as, for example,sodium, potassium, magnesium, calcium, and the like.

“Topical” refers to the delivery of a compound by application to thebody surface and includes, but is not limited to, transdermal deliveryand transmucosal delivery.

“Transdermal” refers to the delivery of a compound by passage throughthe skin and into the blood stream.

“Transmucosal” refers to delivery of a compound by passage of thecompound through the mucosal tissue and into the blood stream.

“Parenteral” refers to delivery of a compound by subcutaneous,intravenous, intramuscular, intracardiac, intradermal, intraperitoneal,intrathecal or intrasternal injection and also includes infusiontechniques.

“Penetration enhancement” or “permeation enhancement” refers to anincrease in the permeability of the skin or mucosal tissue to a selectedpharmacologically active compound such that the rate at which thecompound permeates through the skin or mucosal tissue is increased.

“Carriers” or “vehicles” refers to carrier materials suitable forcompound administration and include any such material known in the artsuch as, for example, any liquid, gel, solvent, liquid diluent,solubilizer, or the like, which is non-toxic and which does not interactwith any components of the composition in a deleterious manner.

“Sustained release” refers to the release of an active compound and/orcomposition such that the blood levels of the active compound aremaintained within a desirable therapeutic range over a period of time.The sustained release formulation can be prepared using any conventionalmethod known to one skilled in the art to obtain the desired releasecharacteristics.

In one embodiment, the invention describes the methods of use of2,5-dihydroxybenzene sulfonic acid compounds of Formula (I) andpharmaceutically acceptable salts thereof:

wherein:

X is a hydrogen, an organic cation or an inorganic cation;

n is an integer from 1 to 2; and

m is an integer from 1 to 2.

The cation X in the 2,5-dihydroxybenzene sulfonic acid compounds ofFormula (I) may be any physiologically acceptable cation known to oneskilled in the art, and include, but are not limited to, those describedin Heinrich Stahl, P., Camille G. Wermuth (Editors), “Handbook ofPharmaceutical Salts Properties, Selections and Use”, Verlag HelveticaChimica Acta, Zurich, Switzerland, Wiley-VCH, Weinheim, Germany, 2002;the disclosures of each of which are incorporated by reference herein intheir entirety. The cation X is selected such that the overall charge ofthe 2,5-dihydroxybenzene sulfonic compounds of Formula I is neutral.

In one embodiment of the invention the inorganic cation ion is sodium,potassium, lithium, calcium or magnesium.

In another embodiment of the invention the organic cation is[NH_(4-p)R_(p)]⁺:

wherein p at each occurrence is independently selected from an integerfrom 0 to 4; and

R is a lower alkyl group.

In another embodiment of the invention, the organic cations are adiethylamine group [H₂N⁺(C₂H₅)₂], piperazine or pyridine.

In other embodiments of the invention, the compounds of Formula (I) are:

2,5-dihydroxybenzene sulfonic acid (dobesilate);

calcium 2,5-dihydroxybenzenesulfonate (calcium dobesilate);

potassium 2,5-dihydroxybenzenesulfonate (potassium dobesilate);

magnesium 2,5-dihydroxybenzenesulfonate (magnesium dobesilate); and

diethylamine 2,5-dihydroxybenzenesulfonate (ethamsylate).

Compounds of the invention that have one or more asymmetric carbon atomsmay exist as the optically pure enantiomers, pure diastereomers,mixtures of enantiomers, mixtures of diastereomers, racemic mixtures ofenantiomers, diastereomeric racemates or mixtures of diastereomericracemates. It is to be understood that the invention anticipates andincludes within its scope all such isomers and mixtures thereof.

The 2,5-dihydroxybenzene sulfonic acid compounds of Formula (I) may alsobe in the form of solvates, particularly in the form of hydrates. Themanufacture of the 2,5-dihydroxybenzene sulfonic acid compounds ofFormula (I) as well as their solvates may be synthesized by one skilledin the art using conventional methods and commercially availablereagents.

The compounds of Formulas (I) can be synthesized by one skilled in theart using conventional methods or are commercially available. Thesynthesis of the compounds of Formula (I) are disclosed in, for example,U.S. Pat. No. 5,082,941; and “The Merck Index” 13^(th) edition, Merck &Co., R. Rahway, N.J., USA, 2001; the disclosures of each of which areincorporated by reference herein in their entirety.

The invention provides compositions comprising at least one compound ofFormula (I) and at least one therapeutic agent, including, but notlimited to, chemotherapeutic agents, steroids, retinoids, antimicrobialcompounds, antioxidants, anti-inflammatory compounds, NMDA receptorantagonists, endothelin antagonists, immunomodulating agents, vitamin Danalogues, salicylic acid, and combinations of two or more thereof. Inone embodiment of the invention, the therapeutic agent does not includeanti-inflammatory compounds. The invention also provides for suchcompositions in a pharmaceutically acceptable carrier.

The compounds of Formula (I) can optionally be used in combination withtherapeutic agents; such as for example, chemotherapeutic agents,steroids, retinoids, antimicrobial compounds, antioxidants,anti-inflammatory compounds, NMDA receptor antagonists, endothelinantagonists, immunomodulating agents, vitamin D analogues, salicylicacid, and combinations of two or more thereof for treating skin cancer;treating cancer of the organs; treating leukemia; improving the efficacyof chemotherapy, radiation therapy and/or cancer immunotherapy; treatingrosacea; and treating psoriasis.

Suitable chemotherapeutic agents, include, but are not limited to,alkylating agents, such as, for example, cyclophosphamide, carmustine,daunorubicin, mechlorethamine, chlorambucil, nimustine, mephalan, andthe like; anthracyclines, such as, for example, daunorubicin,doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, and thelike; taxane compounds, such as, for example, pacitaxel, docetaxel, andthe like; topoisomerase inhibitors, such as, for example, etoposide,teniposide, taluposide, and the like; nucleotide analogs, such as, forexample, azacitidine, azathioprine, capecitabine, cytarabine,doxifluridine, fluorouracil, gemcitabine, mercaptopurine, methotrexate,tioguanine, and the like; platinum based agents, such as, for example,carboplatin, cisplatin, oxaliplatin, and the like; antineoplatic agents,such as, for example, vincristine, leucovorin, lomustine, procarbazine,and the like; hormonal modulators, such as, for example, tamoxifen,finasteride, 5-α-reductase inhibitors, and the like; vinca alkaloids,such as for example, vinblastin, vincristine, vindesine, vinorelbine,and the like. Suitable chemotherapeutic agents are described more fullyin the literature, such as in the Merck Index on CD-ROM, 13^(th)Edition.

In some embodiments of the invention the chemotherapeutic agents are5-fluorouracil, tamoxifin, paclitaxel, cisplatin, carboplatin,carmustine, nimustine, leucovorin, gemcitabine, docetaxel, vincrisfin,vinblastin, vinorelbine, vindesine, irinotecan, vinca alkaloids ortopoisomerase inhibitors.

Suitable steroids, include, but are not limited to, budesonide,dexamethasone, corticosterone, prednisolone, and the like. Suitablesteroids are described more fully in the literature, such as in theMerck Index on CD-ROM, 13^(th) Edition.

In one embodiment of the invention the steroids are dexamethasone,prednisolone and corticosteroids.

Suitable retinoids, include, but are not limited to, natural andsynthetic analogs of vitamin A (retinol), vitamin A aldehyde (retinal),vitamin A acid (retinoic acid (RA)), including all-trans, 9-cis, and13-cis retinoic acid), tretinoin, isotretinoin, alitretinoin,etretinate, acitrtin, tazarotene, bexarotene, and the like. Suitablereinoids are also disclosed in EP 0379367 A2, U.S. Pat. Nos. 4,887,805,4,888,342, 5,514,825; 5,698,700; 5,696,162; 5,688,957; 5,677,451;5,677,323; 5,677,320; 5,675,033; 5,675,024; 5,672,710; 5,688,175;5,663,367; 5,663,357; 5,663,347; 5,648,514; 5,648,503; 5,618,943;5,618,931; 5,618,836; 5,605,915; 5,602,130, 5,648,563; 5,648,385;5,618,839; 5,559,248; 5,616,712; 5,616,597; 5,602,135; 5,599,819;5,556,996; 5,534,516; 5,516,904; 5,498,755; 5,470,999; 5,468,879;5,455,265; 5,451,605; 5,343,173; 5,426,118; 5,414,007; 5,407,937;5,399,586; 5,399,561; 5,391,753, and the like; the disclosures of eachof which are incorporated by reference herein in their entirety.

In some embodiments of the invention the retinoids are retinol, retinal,retinoic acid, tretinoin, isotretinoin or alitretinoin.

Suitable antimicrobial compounds, include, but are not limited to,macrolides, such as, for example, azithromycin, clarithromycin,dirithromycin, erythromycin, milbemycin, troleandomycin, and the like;monbactams, such as, for example, aztreonam, and the like;

Tetracyclins, such as, for example, demeclocyclin, doxycycline,minocycline, oxytetracyclin, tetracycline, and the like;aminoglycosides, such as, for example, amikacin, gentamicin, kanamycin,neomycin, netilmicin, paromomycin, streptomycin, tobramycin, and thelike; carbacephem, such as, for example, loracarbef, and the like;carbapenems, such as, for example, ertapenem, imipenem, meropenem, andthe like; penicillins, such as, for example, amoxicillin, ampicillin,azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin,mezlocillin, nafcillin, penicillin, piperacillin, ticarcillin, and thelike; polypeptides, such as, for example, bacitracin, colistin,polymyxin B, and the like; beta-lactamase inhibitors; cephalosporins,such as, for example, cefaclor, cefamandole, cefoxitin, cefprozil,cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime,cefpodoxime, cefadroxil, ceftazidime, ceftibuten, ceftizoxime,ceftiriaxone, cefazolin, cefixime, cephalexin, cefepime, and the like;quinolones, such as, for example, ciprofloxacin, enoxacin, gatifloxacin,levofloxacin, lomefloxacin, morifloxacin, norfloxacin, ofloxacin,trovafloxacin, and the like; streptogramins; sulfonamides, such as, forexample, mefanide, prontosil, sulfacetamide, sulfamethizole,sulfanilamide, sulfasalazine, sulfisoxazole, trimethoprim,trimethoprim-sultamethoxazole, and the like; and the combination drugssuch as for example, sulfamethoxazole and trimethoprim, and the like.Suitable antimicrobial compounds of the invention are described morefully in the literature, such as in Goodman and Gilman, ThePharmacological Basis of Therapeutics (9th Edition), McGraw-Hill,(1996); Merck Index on CD-ROM, 13^(th) Edition; STN Express, file pharand file registry, the disclosures of each of which are incorporated byreference herein in their entirety.

In some embodiments of the invention, the antimicrobial compounds aretetracycline, erythromycin or clindamycin.

Suitable antioxidants include, but are not limited to, free radicalscavengers, iron chelators, small-molecule antioxidants and antioxidantenzymes, and the like. Suitable iron chelators include, but are notlimited to, deferoxamine, deferiprone, dithiocarbamatem, ethylenediamine tetraacetic acid, and the like. Suitable small-moleculeantioxidants include, but are not limited to, hydralazine compounds,glutathione, ascorbic acid (vitamin C), vitamin E, cysteine,N-acetyl-cysteine, β-carotene, ubiquinone, ubiquinol-10, tocopherols,coenzyme Q, superoxide dismutase mimetics, such as, for example,2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), DOXYL, PROXYL nitroxidecompounds; 4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy (Tempol),M-40401, M-40403, M-40407, M-40419, M-40484, M-40587, M-40588, and thelike. Suitable antioxidant enzymes include, but are not limited to,superoxide dismutase, catalase, glutathione peroxidase, NADPH oxidaseinhibitors, such as, for example, apocynin, aminoguanidine, ONO 1714,S17834 (benzo(b)pyran-4-one derivative), and the like; xanthine oxidaseinhibitors, such as, for example, allopurinol, oxypurinol, amflutizole,diethyldithiocarbamate, 2-styrylchromones, chrysin, luteolin,kaempferol, quercetin, myricetin, isorhamnetin, benzophenones such as2,2′,4,4′-tetrahydroxybenzophenone,3,4,5,2′,3′,4′-hexahydroxybenzophenone and 4,4′-dihydroxybenzophenone;benzothiazinone analogues such as 2-amino-4H-1,3-benzothiazine-4-one,2-guanidino-4H-1,3-benzothiazin-4-one and rhodanine; N-hydroxyguanidinederivative such as, PR5(1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine);6-formylpterin, and the like. The antioxidant enzymes can be deliveredby gene therapy as a viral vector and/or a non-viral vector. Suitableantioxidants are described more fully in the literature, such as inGoodman and Gilman, The Pharmacological Basis of Therapeutics (9thEdition), McGraw-Hill, 1995; and the Merck Index on CD-ROM, ThirteenthEdition; and on STN Express, file phar and file registry.

In some embodiments the antioxidants are ascorbic acid, Vitamin E,apocynin, hydralazine compounds or superoxide dimutase mimetics.

Suitable NSAIDs include, but are not limited to, acetaminophen,acemetacin, aceclofenac, alminoprofen, amfenac, bendazac, benoxaprofen,bromfenac, bucloxic acid, butibufen, carprofen, cinmetacin, clopirac,diclofenac, etodolac, felbinac, fenclozic acid, fenbufen, fenoprofen,fentiazac, flunoxaprofen, flurbiprofen, ibufenac, ibuprofen,indomethacin, isofezolac, isoxepac, indoprofen, ketoprofen, lonazolac,loxoprofen, metiazinic acid, mofezolac, miroprofen, naproxen, oxaprozin,pirozolac, pirprofen, pranoprofen, protizinic acid, salicylamide,sulindac, suprofen, suxibuzone, tiaprofenic acid, tolmetin, xenbucin,ximoprofen, zaltoprofen, zomepirac, aspirin, acemetcin, bumadizon,carprofenac, clidanac, diflunisal, enfenamic acid, fendosal, flufenamicacid, flunixin, gentisic acid, ketorolac, meclofenamic acid, mefenamicacid, mesalamine, prodrugs thereof, and the like. Suitable NSAIDs aredescribed more fully in the literature, such as in Goodman and Gilman,The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill,1995, Pgs. 617-657; the Merck Index on CD-ROM, 13^(th) Edition; and inU.S. Pat. Nos. 6,057,347 and 6,297,260 assigned to NitroMed. Inc., thedisclosures of which are incorporated herein by reference in theirentirety.

In some embodiments the NSAIDs are acetaminophen, diclofenac,flurbiprofen, ibuprofen, indomethacin, ketoprofen, naproxen or aspirin.

Suitable N-methyl-D-aspartate (NMDA) receptor antagonists, include, butare not limited to, ketamine, dextromethorphan, memantine, amantadine,nitrous oxide, Gacyclidine and the like.

In some embodiments the NMDA receptor antagonists are dextromethorphan.

Suitable endothelin antagonists include, but are not limited to,atrasentan, bosentan, darusentan, enrasentan, sitaxsentan, sulfonamideendothelin antagonists, tezosentan, BMS 193884, BQ-123, SQ 28608, andthe like. Suitable endothelin antagonists are described more fully inthe literature, such as in Goodman and Gilman, The Pharmacological Basisof Therapeutics (9th Edition), McGraw-Hill, 1995; and the Merck Index onCD-ROM, Thirteenth Edition; and on STN Express, file phar and fileregistry.

Suitable immunomodulating agents, include, but are not limited to,interferon α IIb, autologous granulocyte macrophagecolony stimulatingfactor, APC 8015 (Provenge), cancer vaccines, anti-senseoligonucleotides, bacillus of Calmette-Guerin (BCG), and the like.

Suitable vitamin D analogues, include but are not limited to, vitamin D3analogues such as, cholecalciferol, calcidiol, calcitriol, and the like.

The invention describes methods for treating skin cancer; treatingcancer of an organ; treating leukemia; and improving the efficacy ofchemotherapy, radiation therapy and/or cancer immunotherapy in a patientin need thereof comprising administering to the patient in need thereofan effective amount of the compounds and/or compositions describedherein. For example, the patient can be administered an effective amountof at least one 2,5-dihydroxybenzene sulfonic acid compound. In anotherembodiment, the patient can be administered an effective amount of atleast one 2,5-dihydroxybenzene sulfonic acid compound, and, at least onetherapeutic agent, including but not limited to, such as, for example,chemotherapeutic agents, steroids, retinoids, antimicrobial compounds,antioxidants, anti-inflammatory compounds, NMDA receptor antagonists,endothelin antagonists, immunomodulating agents, vitamin D analogues,salicylic acid, and combinations of two or more thereof. The2,5-dihydroxybenzene sulfonic acid compounds and/or therapeutic agentscan be administered separately or as components of the same compositionin one or more pharmaceutically acceptable carriers.

In one embodiment of the invention for the methods for treating skincancer; treating cancer of an organ; treating leukemia; and improvingthe efficacy of chemotherapy, radiation therapy and/or cancerimmunotherapy the therapeutic agent is selected from the groupconsisting of chemotherapeutic agents, steroids, antimicrobialcompounds, antioxidants, anti-inflammatory compounds, NMDA receptorantagonists, endothelin antagonists, immunomodulating agents, andcombinations of two or more thereof.

The invention describes methods for treating rosacea in a patient inneed thereof comprising topically administering to the patient in needthereof an effective to amount of the compounds and/or compositionsdescribed herein. For example, the patient can be administered aneffective amount of at least one 2,5-dihydroxybenzene sulfonic acidcompound. In another embodiment, the patient can be administered aneffective amount of at least one 2,5-dihydroxybenzene sulfonic acidcompound, and, at least one therapeutic agent, including but not limitedto, such as, for example, steroids, retinoids, antimicrobial compounds,antioxidants, anti-inflammatory compounds, and combinations of two ormore thereof. The 2,5-dihydroxybenzene sulfonic acid compounds and/ortherapeutic agents can be administered separately or as components ofthe same composition in one or more pharmaceutically acceptablecarriers.

In one embodiment of the invention for the methods for treating rosaceathe therapeutic agent is selected from the group consisting of steroids,retinoids, antimicrobial compounds, antioxidants, anti-inflammatorycompounds, vitamin D analogues, salicylic acid, and combinations of twoor more thereof.

The invention describes methods for treating psoriasis in a patient inneed thereof comprising administering to the patient in need thereof aneffective amount of the compounds and/or compositions described herein.For example, the patient can be administered an effective amount of atleast one 2,5-dihydroxybenzene sulfonic acid compound. In anotherembodiment, the patient can be administered an effective amount of atleast one 2,5-dihydroxybenzene sulfonic acid compound, and, at least onetherapeutic agent, including but not limited to, such as, for example,steroids, retinoids, antimicrobial compounds, antioxidants,anti-inflammatory compounds, and combinations of two or more thereof.The 2,5-dihydroxybenzene sulfonic acid compounds and/or therapeuticagents can be administered separately or as components of the samecomposition in one or more pharmaceutically acceptable carriers.

In one embodiment of the invention for the methods for treatingpsoriasis the therapeutic agent is selected from the group consisting ofsteroids, retinoids, antimicrobial compounds, antioxidants,anti-inflammatory compounds, vitamin D analogues, salicylic acid, andcombinations of two or more thereof.

When administered separately, the 2,5-dihydroxybenzene sulfonic acidcompound, can be administered about the same time as part of the overalltreatment regimen i.e., as a combination therapy. “About the same time”includes administering the 2,5-dihydroxybenzene sulfonic acid compound,simultaneously, sequentially, at the same time, at different times onthe same day, or on different days, as long as they are administered aspart of an overall treatment regimen, i.e., combination therapy or atherapeutic cocktail.

When administered in vivo, the compounds and compositions of theinvention can be administered in combination with pharmaceuticallyacceptable carriers and in dosages described herein. When the compoundsand compositions of the invention are administered as a combination ofat least one 2,5-dihydroxybenzene sulfonic acid compound and/or at leastone therapeutic agent, they can also be used in combination with one ormore additional compounds which are known to be effective against thespecific disease state targeted for treatment. The therapeutic agentsand/or other additional compounds can be administered simultaneouslywith, subsequently to, or prior to administration of the2,5-dihydroxybenzene sulfonic acid compound.

The compounds and compositions of the invention can be administered byany available and effective delivery system including, but not limitedto, orally, bucally, parenterally, by inhalation, by topicalapplication, or rectally (e.g., by the use of suppositories) in dosageunit formulations containing conventional nontoxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles, as desired.

In one embodiment of the invention the 2,5-dihydroxybenzene sulfonicacid compounds of the invention are administered orally, bucally,parenterally, by inhalation, by topical application or rectally for thetreatment of skin cancer; cancer of an organ; leukemia; and improvingthe efficacy of chemotherapy, radiation therapy and/or cancerimmunotherapy. In another embodiment of the invention the2,5-dihydroxybenzene sulfonic acid compounds are administered orally,parenterally or by topical application for the treatment of skin canceror improving the efficacy of chemotherapy, radiation therapy and/orcancer immunotherapy. In yet another embodiment of the invention the2,5-dihydroxybenzene sulfonic acid compounds are administered orally,bucally, parenterally or by topical application for the treatment ofcancer of an organ. In one embodiment of the invention the2,5-dihydroxybenzene sulfonic acid compounds are administered orally,bucally or parenterally for the treatment of leukemia.

In some embodiments of the invention the 2,5-dihydroxybenzene sulfonicacid compounds are administered orally, bucally, parenterally ortopically for the treatment of psoriasis.

Solid dosage forms for oral administration can include capsules,sustained-release capsules, tablets, sustained release tablets, chewabletablets, sublingual tablets, effervescent tablets, pills, suspensions,powders, granules and gels. In such solid dosage forms, the activecompounds can be admixed with at least one inert diluent such assucrose, lactose or starch. Such dosage forms can also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, effervescent tablets, and pills, the dosage forms can alsocomprise buffering agents. Soft gelatin capsules can be prepared tocontain a mixture of the active compounds or compositions of theinvention and vegetable oil. Hard gelatin capsules can contain granulesof the active compound in combination with a solid, pulverulent carriersuch as lactose, saccharose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives of gelatin. Tablets and pillscan be prepared with enteric coatings.

Liquid dosage forms for oral administration can include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions can also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

Suppositories for vaginal or rectal administration of the compounds andcompositions of the invention can be prepared by mixing the compounds orcompositions with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at room temperature butliquid at rectal temperature, such that they will melt in the rectum andrelease the compounds and compositions.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing agents, wetting agents and/or suspendingagents. The sterile injectable preparation can also be a sterileinjectable solution or suspension in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that can be used are water,Ringer's solution, and isotonic sodium chloride solution. Sterile fixedoils are also conventionally used as a solvent or suspending medium.

Topical administration of the compounds and compositions invention canbe in the form of creams, gels, lotions, liquids, ointments, sprayssolutions, dispersions, solid sticks, emulsions, microemulsions, eyedrops, nose drops, ear drops, and the like, that can be formulatedaccording to the conventional methods using suitable excipients, suchas, for example, emulsifiers, surfactants, thickening agents, sunscreenagents, moisturizers, cooling agents, skin lightening agent, skinconditioning agents, skin protectants, emollients, humectants,colorants, and combinations of two or more thereof.

The compounds and compositions of the invention can be transdermallyadministered in the form of transdermal patches or iontophoresisdevices. Other components can optionally be incorporated into thetransdermal patches. For example, compositions and/or transdermalpatches can be formulated with one or more preservatives orbacteriostatic agents including, but not limited to, methylhydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkoniumchloride, and the like. Woven pads or rolls of bandaging material, e.g.,gauze, can be impregnated with the compositions in solution, lotion,cream, ointment or other such form can also be used for topicalapplication. In one embodiment, the compositions of the invention areadministered as a transdermal patch. In another embodiment compositionsof the invention are administered as a sustained-release transdermalpatch. The transdermal patches of the invention can include anyconventional forms such as, for example, adhesive matrix, polymericmatrix, reservoir patch, matrix or monolithic-type laminated structure,and are generally comprised of one or more backing layers, adhesives,penetration enhancers, an optional rate controlling membrane and arelease liner which is removed to expose the adhesives prior toapplication. Polymeric matrix patches also comprise a polymeric-matrixforming material. Suitable transdermal patches are described in moredetail in, for example, U.S. Pat. Nos. 5,262,165, 5,948,433, 6,010,715and 6,071,531, the disclosure of each of which are incorporated hereinin their entirety.

The compositions of this invention can further include conventionalexcipients, i.e., pharmaceutically acceptable organic or inorganiccarrier substances suitable for parenteral application which do notdeleteriously react with the active compounds. Suitable pharmaceuticallyacceptable carriers include, for example, water, salt solutions,alcohol, vegetable oils, polyethylene glycols, gelatin, lactose,amylose, magnesium stearate, talc, surfactants, silicic acid, viscousparaffin, perfume oil, fatty acid monoglycerides and diglycerides,petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, and the like. The pharmaceutical preparations canbe sterilized and if desired, mixed with auxiliary agents, e.g.,lubricants, preservatives, stabilizers, wetting agents, emulsifiers,salts for influencing osmotic pressure, buffers, colorings, flavoringand/or aromatic substances and the like which do not deleteriously reactwith the active compounds. For parenteral application, particularlysuitable vehicles consist of solutions, preferably oily or aqueoussolutions, as well as suspensions, emulsions, or implants. Aqueoussuspensions may contain substances which increase the viscosity of thesuspension and include, for example, sodium carboxymethyl cellulose,sorbitol and/or dextran. Optionally, the suspension may also containstabilizers.

The composition, if desired, can also contain minor amounts of wettingagents, emulsifying agents and/or pH buffering agents. The compositioncan be a liquid solution, suspension, emulsion, tablet, pill, capsule,sustained release formulation, or powder. The composition can beformulated as a suppository, with traditional binders and carriers suchas triglycerides. Oral formulations can include standard carriers suchas pharmaceutical grades of mannitol, lactose, starch, magnesiumstearate, sodium saccharine, cellulose, magnesium carbonate, and thelike.

Various delivery systems are known and can be used to administer thecompounds or compositions of the invention, including, for example,encapsulation in liposomes, microbubbles, emulsions, microparticles,microcapsules and the like. The required dosage can be administered as asingle unit or in a sustained release form.

Suitable sustained-release forms as well as the materials and methodsfor their preparation are described in, for example, “Modified-ReleaseDrug Delivery Technology”, Rathbone, M. J. Hadgraft, J. and Roberts, M.S. (Eds.), Marcel Dekker, Inc., New York (2002); “Handbook ofPharmaceutical Controlled Release Technology”, Wise, D. L. (Ed.), MarcelDekker, Inc. New York, (2000); “Controlled Drug Delivery”, Vol. 1, BasicConcepts, Bruck, S. D. (Ed.), CRC Press Inc., Boca Raton (1983) and fromTakada, K. and Yoshikawa, H., “Oral Drug delivery”, Encyclopedia ofControlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc.,New York (1999), Vol. 2, 728-742; Fix, J., “Oral drug delivery, smallintestine and colon”, Encyclopedia of Controlled Drug Delivery,Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2,698-728; the disclosures of each of which are incorporated herein byreference in their entirety.

In one embodiment of the invention, the orally administrable form of the2,5-dihydroxybenzene sulfonic acid compounds is in a sustained-releaseform further comprising at least one coating or matrix. Thesustained-release coating or matrix, include, but are not limited to,modified, water-insoluble, natural, semisynthetic or synthetic polymers,natural, semisynthetic or synthetic waxes, fats, fatty alcohols, fattyacid, plasticizers, or a combination of two or more thereof.

Suitable water-insoluble polymers, include, but are not limited to,acrylic resins, such as, for example, poly(meth)acrylates, poly(C₁₋₄)alkyl(meth)acrylates, poly(C₁₋₄)dialkylamino (C₁₋₄) alkyl(meth)acrylatesand/or copolymers, and the like, and combinations of two or morethereof; copolymers of ethyl acrylate and methyl methacrylate with amonomer molar ratio of 2:1 (EUDRAGIT NE30DM), copolymers of ethylacrylate, methylmethacrylate and trimethylammonium ethylmethacrylate-chloride with a monomer molar ratio of 1:2:0.1 (EUDRAGITRS®), copolymers of ethyl acrylate, methyl methacrylate andtrimethylammonium ethyl methacrylate-chloride with a monomer molar ratioof 1:2:0.2 (EUDRAGIT RL®), and the like, and combinations of two or morethereof.

Suitable water-insoluble polymers, include, but are not limited to,cellulose derivatives, such as, for example, alkyl celluloses, ethylcellulose, cellulose esters, cellulose acetate, AQUACOAT®, SURELEASE®,and the like.

Suitable natural, semisynthetic or synthetic waxes, fats or fattyalcohols, include, but are not limited to, carnauba wax, beeswax,glycerol monostearate, glycerol monobehenate, glycerolditripalmitostearate, microcrystalline wax, cetyl alcohol, cetylstearylalcohol, and the like, and combinations of two or more thereof.

Suitable plasticizers, include, but are not limited to, lipophilicdiesters of a C₆-C₄₀ aliphatic or aromatic dicarboxylic acids, C₁-C₈aliphatic alcohols, such as, for example, dibutyl phthalate, diethylphthalate, dibutyl sebacate, diethyl sebacate, and the like; hydrophilicor lipophilic citric acid esters, such as, for example, triethylcitrate, tributyl citrate, acetyltributyl citrate, acetyltriethylcitrate, and the like; polyethylene glycols, propylene glycol, glycerolesters, such as, for example, triacetin, MYVACET® (acetylated mono- anddiglycerides, C₂₃H₄₄O₅ to C₂₅H₄₇O), medium-chain triglycerides(MIGLYOL®), oleic acid or mixtures of at least two of said plasticizers.The sustained-release formulations may comprise one or more plasticisersin amounts of, about 5 to about 50 wt. % based on the amount ofpolymer(s) used.

The sustained-release formulations may also contain other conventionalexcipients known to one skilled in the art, such as, for example,lubricants, colored pigments, surfactants, and the like. Thesustained-release formulations may also contain an enteric coating.

Suitable enteric coatings, include, but are not limited to, methacrylicacid/methyl methacrylate copolymers with a monomer molar ratio of 1:1(EUDRAGIT L®), methacrylic acid/methyl methacrylate copolymers with amonomer molar ratio of 1:2 (EUDRAGIT S®), methacrylic acid/ethylacrylate copolymers with a monomer molar ratio of 1:1 (EUDRAGITL30D-55®), methacrylic acid/methyl acrylate/methyl methacrylatecopolymers with a monomer molar ratio of 7:3:1 (EUDRAGIT FS®), shellac,hydroxypropyl methyl cellulose, acetate-succinates, celluloseacetate-phthalates or a combination of two or more thereof. Theseenteric coating can optionally also be used in combination with thewater-insoluble poly (meth)acrylates described herein. In one embodimentthe enteric coatings are used in combination with EUDRAGIT NE30D®,and/or EUDRAGIT RL® and/or EUDRAGIT RS®.

The enteric coatings may be applied using conventional processes knownto those skilled in the art, as described in, for example, Johnson, J.L., “Pharmaceutical tablet coating”, Coatings Technology Handbook(Second Edition), Satas, D. and Tracton, A. A. (Eds), Marcel Dekker,Inc. New York, (2001), 863-866; Carstensen, T., “Coating Tablets inAdvanced Pharmaceutical Solids”, Swarbrick, J. (Ed.), Marcel Dekker,Inc. New York (2001), 455468; Leopold, C. S., “Coated dosage forms forcolon-specific drug delivery”, Pharmaceutical Science & TechnologyToday, 2 (5), 197-204 (1999), Rhodes, C. T. and Porter, S. C., Coatings,in Encyclopedia of Controlled Drug Delivery. Mathiowitz, E. (Ed.), JohnWiley & Sons, Inc., New York (1999), Vol. 1, 299-311; the disclosures ofeach of which are incorporated herein by reference in their entirety.

In one embodiment of the invention, the sustained release formulationscomprising at least one 2,5-dihydroxybenzene sulfonic acid compound isin an immediate release form and in a sustained release form in the sameformulation. The formulation may further comprises at least onetherapeutic agent, such as for example, chemotherapeutic agents,steroids, retinoids, antimicrobial compounds, antioxidants,anti-inflammatory compounds, NMDA receptor antagonists, endothelinantagonists, immunomodulating agents, vitamin D analogues, salicylicacid, and combinations of two or more thereof.

While individual needs may vary, determination of optimal ranges foreffective amounts of the compounds and/or compositions is within theskill of the art. Generally, the dosage required to provide an effectiveamount of the compounds and compositions, which can be adjusted by oneof ordinary skill in the art, will vary depending on the age, health,physical condition, sex, diet, weight, extent of the dysfunction of therecipient, frequency of treatment and the nature and scope of thedysfunction or disease, medical condition of the patient, the route ofadministration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound used, whether a drug delivery system is used, and whether thecompound is administered as part of a drug combination.

The amount of a given 2,5-dihydroxy benzene sulfonic acid compound thatwill be effective in the treatment of a particular disorder or conditionwill depend on the nature of the disorder or condition, and can bedetermined by standard clinical techniques, including reference toGoodman and Gilman, supra; The Physician's Desk Reference, MedicalEconomics Company, Inc., Oradell, N.J., 1995; and Drug Facts andComparisons, Inc., St. Louis, Mo., 1993; the disclosures of each ofwhich are incorporated herein by reference in their entirety. Theprecise dose to be used in the formulation will also depend on the routeof administration, and the seriousness of the disease or disorder, andshould be decided by the physician and the patient's circumstances.

In one embodiment, the 2,5-dihydroxybenzene sulfonic acid compounds ofFormula (I) can be orally, bucally or parentally administered in anamount of about 0.05 g per day to about 50 g per day. In particularembodiments, the 2,5-dihydroxybenzene sulfonic acid compounds of Formula(I) can be orally, bucally or parentally administered in an amount ofabout 0.10 g per day to about 25 g per day. In more particularembodiments, the 2,5-dihydroxybenzene sulfonic acid compounds of Formula(I) can be orally, bucally or parentally administered in an amount ofabout 0.25 g per day to about 10 g per day. In a more particularembodiment, 2,5-dihydroxybenzene sulfonic acid compounds of Formula (I)can be administered in an amount of about 0.5 g per day to about 5 g perday. In an even more particular embodiment, 2,5-dihydroxybenzenesulfonic acid compounds of Formula (I) can be administered in an amountof about 0.75 g per day to about 2.5 g per day. In another particularembodiment, 2,5-dihydroxybenzene sulfonic acid compounds of Formula (I)can be administered in an amount of about 1 g per day to about 1.5 g perday. The particular amounts of the 2,5-dihydroxybenzene sulfonic acidcompounds of Formula (I) can be administered can be administered as asingle dose once a day; or in multiple doses several times throughoutthe day; or as a sustained-release oral formulation. In one embodimentof the invention the 2,5-dihydroxybenzene sulfonic acid compounds ofFormula (I) is administered orally, bucally or parentally as about 50 g,25 g, 10 g, 5 g, 1 g, 0.75 g, 0.5 g, 0.25 g or 0.1 g once per day (q.d).In another embodiment of the invention the 2,5-dihydroxybenzene sulfonicacid compounds of Formula (I) is administered orally, bucally orparentally as about 50 g, 25 g, 10 g, 5 g, 1 g, 0.75 g, 0.5 g, 0.25 g or0.1 g twice per day (b.i.d). In yet another embodiment of the inventionthe 2,5-dihydroxybenzene sulfonic acid compounds of Formula (I) isadministered orally, bucally or parentally as about 50 g, 25 g, 10 g, 5g, 1 g, 0.75 g, 0.5 g, 0.25 g or 0.1 g three times per day (t.i.d.). Inanother embodiment of the invention the 2,5-dihydroxybenzene sulfonicacid compounds of Formula (I) is administered orally, bucally orparentally as about 50 g, 25 g, 10 g, 5 g, 1 g, 0.75 g, 0.5 g, 0.25 g or0.1 g four times per day.

In particular embodiments, the 2,5-dihydroxybenzene sulfonic acidcompounds of Formula (I) can be topically administered in a formulationcomprising an amount of about 0.001% to about 30% (w/w) of the2,5-dihydroxybenzene sulfonic acid compounds of Formula (I). In a moreparticular embodiment, the 2,5-dihydroxybenzene sulfonic acid compoundsof Formula (I) can be topically administered in a formulation comprisingan amount of about 0.01% to about 20% (w/w) of the 2,5-dihydroxybenzenesulfonic acid compounds of Formula (I). In an even more particularembodiment, the 2,5-dihydroxybenzene sulfonic acid compounds of Formula(I) can be topically administered in a formulation comprising an amountof about 0.1% to about 15% (w/w) of the 2,5-dihydroxybenzene sulfonicacid compounds of Formula (I). In a more particular embodiment, the2,5-dihydroxybenzene sulfonic acid compounds of Formula (I) can betopically administered in a formulation comprising an amount of about0.5% to about 10% (w/w) of the 2,5-dihydroxybenzene sulfonic acidcompounds of Formula (I). In another particular embodiment, the2,5-dihydroxybenzene sulfonic acid compounds of Formula (I) can betopically administered in a formulation comprising an amount of about 1%to about 5% (w/w) of the 2,5-dihydroxybenzene sulfonic acid compounds ofFormula (I). In a more particular embodiment, the 2,5-dihydroxybenzenesulfonic acid compounds of Formula (I) can be topically administered ina formulation comprising an amount of about 2.5% to about 4% (w/w) ofthe 2,5-dihydroxybenzene sulfonic acid compounds of Formula (I). Thetopical formulation comprising the 2,5-dihydroxybenzene sulfonic acidcompounds of Formula (I) can be administered as a single dose once aday; or in multiple doses several times throughout the day. In oneembodiment of the invention the topical formulation comprising about30%, 20%, 15%. 10%, 5%, 2.5%, 1%, 0.5%, 0.1% or 0.001% of the2,5-dihydroxybenzene sulfonic acid compounds of Formula (I) isadministered four times per day. In another embodiment of the inventionthe topical formulation comprising about 30%, 20%, 15%. 10%, 5%, 2.5%,1%, 0.5%, 0.1% or 0.001% of the 2,5-dihydroxybenzene sulfonic acidcompounds of Formula (I) is administered three times per day (t.i.d). Inyet another embodiment of the invention the topical formulationcomprising about 30%, 20%, 15%. 10%, 5%, 2.5%, 1%, 0.5%, 0.1% or 0.001%of the 2,5-dihydroxybenzene sulfonic acid compounds of Formula (I) isadministered two times per day (b.i.d). In another embodiment of theinvention the topical formulation comprising about 30%, 20%, 15%. 10%,5%, 2.5%, 1%, 0.5%, 0.1% or 0.001% of the 2,5-dihydroxybenzene sulfonicacid compounds of Formula (I) is administered once times per day (qd).

EXAMPLES

The following non-limiting examples further describe and enable one ofordinary skill in the art to make and use the present invention.

In all the examples, 2,5-dihydroxybenzene sulfonate (DHBS) refers to thepotassium salt of 2,5-dihydroxybenzene sulfonic acid.

Example 1 2,5-Dihydroxybenzene Sulfonic Acid Potentiates Chemotherapy

C6 cells cultured in vitro under the same conditions as described in PCTApplication No. 2005/077352. 1.1×10³ cells per well were cultured in24-well plates. Three types of treatment were conducted: a) 24 hoursafter seeding, the cells were separately treated with each of thefollowing medicines; cisplatin (5 μg/ml), vincristine (0.1 μg/ml),paclitaxel (5 μg/ml) and 5-fluorouracil (100 μg/ml); b) 24 hours afterseeding, the cells were treated with a combination of2,5-dihydroxybenzene sulfonic acid (100 μM) and each one of thefollowing agents; cisplatin (5 μg/ml) vincristine (0.1 μg/ml),paclitaxel (5 μg/ml) and 5-fluorouracil (100 μg/ml); c) at the time ofseeding (Day 0), the cells were pre-treated with 2,5-dihydroxybenzenesulfonic acid (100 μM). The next day the cultures were also treated witheach one of the following agents: cisplatin (5 μg/ml) vincristine (0.1μg/ml), paclitaxel (5 μg/ml) and 5-fluorouracil (100 μg/ml). Thecontrolled cultures did not receive any treatment for 2 days. After 48hours (day 2), the cells were evaluated in all the cultures. This studywas carried out in triplicate independent experiments and was repeatedthree times.

FIGS. 1 (A, B, C and D) shows the histograms of the experimentsperformed to evaluate the effect of the 2,5-dihydroxybenzene sulfonicacid to potentate cytostatic agents. Treatment with cysplatin,vincristine and 5-fluorouracil produced an inhibition of 50% in theproliferation of C6 cells, while treatment with paclitaxel resulted in67% inhibition of the cellular proliferation. The treatment with thecombination of the 2,5-dihydroxybenzene sulfonic acid and the cytostaticagents (cysplatin, vincristine and 5-fluorouracil) resulted in an 84%inhibition in cellular proliferation. The combination treatment with2,5-dihydroxybenzene sulfonic acid and paclitaxel resulted in 86%inhibition of the cellular proliferation. When the cellular cultureswere pre-treated with the 2,5-dihydroxybenzene sulfonic acid followed bythe cytostatic agents: cysplatin, vincristine and 5-fluorouracil, 90%inhibition was obtained in the cell proliferation. When paclitaxel wasused, the inhibition in cellular proliferation was up to 92%.

The results demonstrate that the simultaneous treatment of the2,5-dihydroxybenzene sulfonic acid with the chemotherapeutic agents,increases their therapeutic efficacy and the chemical potentiationeffect is higher when the cells have been pre-treated with2,5-dihydroxybenzene sulfonic acid. These data support the use of the2,5-dihydroxybenzene sulfonic acid as an aid in the treatment associatedwith chemical therapy and radiotherapy.

Example 2 2,5-Dihydroxybenzene Sulfonate Increases the Chemo Sensitivityin Rat C6 Glioma Cells

Cultures of rat glioma C6 cells were grown as described in Cuevas P etal. Neurol. Res., 27: 797-800 (2005). Briefly, cells were grown asadherent cells in Dulbecco modified Eagle medium supplemented with 1%(v/v) fatal bovine serum, 10 μg/ml streptomycin and 10 units/mlpenicillin (DMEM). Tumour cells were set up in 24-well cell cultureplates, at a density of 10,000 cells per well and incubated at 37° C. ina humidified chamber with 5% CO₂. Cells were either treated with2,5-dihydroxybenzene sulfonate (100 μM in DMEM) or with DMEM (controls).Eighty hours after the addition of 2,5-dihydroxybenzene sulfonate, thecells were either treated or not treated with the cytostatic agents,cisplatin (5 μg/ml in DMEM), vincristine (0.5 μg/ml in DMEM), paclitaxel(5 μg/ml in DMEM), 5-fluorouracil (100 μg/ml in DMEM) and irinotecan(CPT-11; 0.1 μg/ml in DMEM). After an additional two days theproliferation of the glioma cells was assessed using crystal violetstaining of fixed cells. The cell number was computed by the amount ofretained dye determined spectroscopically at 595 nm after itsresolubilization. Cell viability was estimated by trypan blue dye assay.

As shown in FIG. 2 all the cytostatic agents used, except foririnotecan, partially inhibited C6 glioma cell proliferation. However, amarkedly enhanced inhibition of proliferation of glioma cells wasobserved in all cases when the cells were pre-treated with2,5-dihydroxybenzene sulfonate. Thus, 2,5-dihydroxybenzene sulfonateenhances the sensitivity of glioma cells to the anti-proliferativeaction of the cytostatic agents.

Example 3 2,5-Dihydroxybenzene Sulfonate Increases the Efficacy ofIrinotecan (CPT-11) in Rat Glioma

Cultures of rat glioma C6 cells were grown as described in Cuevas P etal. Neurol. Res., 27: 797-800 (2005). Confluent C6 cells cultured in 75cm² flasks were detached and implanted into the left frontal lobe ofanaesthetized rats using a stereotactic device. The implantation of the10⁶ glioma cells was accomplished by means of a Hamilton syringe coupledto a glass pipette (40-60 μm in diameter) through a small orificeperformed in the cranium by a stainless steel needle. FIG. 3, panels A,B and C shows the magnetic resonance image of the rat brain two weeksafter implantation. Ten days after the existence of a tumour wasconfirmed, rats were randomly assigned to receive or not receive2,5-dihydroxybenzene sulfonate (200 mg/kg/day in saline; i.p) throughoutthe period of observation. Two days after starting the treatment with2,5-dihydroxybenzene sulfonate, the rats were treated with irinotecan(CPT-11; 10 mg/kg/day; i.p. Campto® solution (20 mg/ml; Aventis, Madrid,Spain) or saline in two four-days cycles separated by a four-daysresting period. After the treatment (6 weeks after implantation ofglioma cells), FIG. 2, panels D, E and F show the magnetic resonanceimages of the brain obtained from rats treated with irinotecan,2,5-dihydroxybenzene sulfonate or the combination of irinotecan and2,5-dihydroxybenzene sulfonate respectively. n=3 rats (irinotecan); n=4rats (DHBS); n=4 rats (irinotecan+DHBS)

As can be seen in FIG. 3, panel D, six weeks after the implantation ofglioma cells, the rats treated only with irinotecan had a large sizedbrain tumour, surpassing the size of the rat cerebral hemisphere. Ratstreated only with 2,5-dihydroxybenzene sulfonate presented a braintumour smaller than that observed in the irinotecan-treated rat, andwith altered distribution of the contrast agent (FIG. 3, panel E). Therat treated with 2,5-dihydroxybenzene sulfonate plus irinotecan had asmaller sized brain tumour than that observed in the other twotreatments, with poor distribution of the contrast agent (FIG. 3, panelF). Thus, the treatment with 2,5-dihydroxybenzene sulfonate increasesthe efficacy of the cytostatic agent, irinotecan, to reduce theprogression of an established orthotropic glioma.

Example 4 Effect of 2,5-Dihydroxybenzene Sulfonate on the Progression ofEstablished Rat Subcutaneous Gliomas

Confluent C6 cells cultured as described in Example 2 were detached andsubcutaneously implanted under the dorsal skin in anaesthetized rats.One week after the implantation of the tumour cells, the rats wererandomly assigned to receive intra-tumoural injection of2,5-dihydroxybenzene sulfonate (100 mg/kg in saline) or saline twice aday. Ten days after starting the treatment, subcutaneous heterotopicgliomas were removed from the rats and their volumes were calculated.

FIG. 4 shows that the tumour obtained collected from saline-treated rats(a) was markedly larger than the tumours obtained from rats treated byintra-tumoural injection of 2,5-dihydroxybenzene sulfonate (b). FIG. 5shows that the volume of tumours from rats intraperitoneally treatedwith 2,5-dihydroxybenzene sulfonate was significantly reduced whencompared to saline-treated rats thereby demonstrating the inhibitoryeffect of 2,5-dihydroxybenzene sulfonate in the progression ofestablished heterotopic gliomas.

Example 5 Effect of 2,5-Dihydroxybencene Sulfonate on Melanoma Growth

New Zealand White rabbits (weight 3.0±0.5 kg) were used. All surgicalprocedures were performed under intramuscular general anaesthesia(xylazine hydrochloride, 5 mg/kg). The rabbit eyes were treated withlicalin, an ophthalmic solution for surface anaesthesia. Using asurgical microscope a millimeter fragment of human melanoma biopsy wasimplanted into a pocket made in the stroma of the cornea. About 2 mmaway from the limbal origin of the cornea. An osmotic minipump (Alzet2002, Alza Corporation, Palo Alto, Calif., USA) was implantedsubcutaneously into the rabbit neck region to ensure continuous infusionof either saline or 2,5-dihydroxybenzene sulfonate (200 mg/ml insaline). A delivery catheter was placed free in the sclera through atunnel performed into the superior tharsus to deliver either2,5-dihydroxybenzene sulfonate or saline at a constant rate of 0.5 μl/h.To ensure a constant ocular concentration of 2,5-dihydroxybenzenesulfonate a tharsoraphy was performed. After 14 days of therapy, corneaswere removed and processed for histological examination (10% formalinfixation, alcohol dehydration and paraffin embedding). FIG. 6 shows thatthe melanoma in rats treated with 2,5-dihydroxybenzen sulfonate (panelsC and D) was reduced relative to rabbits treated with saline (panels Aand B).

Example 6 Effect of 2,5 Dihydroxybenzene Sulfonate on Basal CellCarcinoma

2,5-dihydroxybenzene sulfonate cream (2.5%) was applies topically twicea day to the lesions of a patient with basal cell carcinoma (BCC). Asshown in FIG. 7, the lesion in the patient with facial infiltrative BCCwere cleared after 4 weeks of treatment, with no recurrence for a twoyears period after treatment (FIG. 8). Treatment with2,5-dihydroxybenzene sulfonate (2.5%), cleared the histopathologicalsigns of BCC and increased the rate of apoptosis (FIG. 9). Topicaladministration of 2,5-dihydroxybenzene sulfonate cream (2.5%) twice aday for two months also cleared the lesion in two other patients withinfiltrative BCC, showing no recurrence six months after treatmentcompletion (FIG. 10). BCC tumour lesions of a nodular type from twoadditional patients disappeared after six months of treatment withtopical administration of 2,5-dihydroxybenzene sulfonate cream (2.5%)twice a day (FIG. 11). Topical administration of 2,5-dihydroxybenzenesulfonate cream twice a day inhibited proliferation rate in dermis andepidermis in BCC specimens from 5 different patients (FIGS. 12 and 13).In addition, the treatment with 2,5-dihydroxybenzene sulfonate cream(2.5%) inhibited vascularization and increased apoptosis rate in these 5patients (FIGS. 14 and 15).

Example 7

Effect of 2,5-Dihydroxybenzene Sulfonate on Rosacea

A woman with facial rosacea was treated twice a day with2,5-dihydroxybenzene sulfonate cream (2.5%) by topical application inthe affected area for two months. As shown in FIG. 16 topical treatmentwith 2,5-dihydroxybenzene sulfonate cream led to a significantimprovement in erythema and telangectasia. Furthermore, the symptoms offlushing, burning and stinging sensations were all reduced aftertreatment, with no recurrence one year after stopping the treatment.

Example 8 Effect of 2,5-Dihydroxybenzene Sulfonate on Rosacea

A woman with facial rosacea was treated twice a day with2,5-dihydroxybenzene sulfonate cream (2.5%) by topical application inthe affected area for three weeks. As shown in FIG. 17 topical treatmentwith 2,5-dihydroxybenzene sulfonate cream led to a significantimprovement in erythema and telangectasia.

Example 9 Effect of 2,5-Dihydroxybenzene Sulfonate on Psoriatic Lesions

The potassium salt of 2,5-dihydroxybenzene sulfonic acid was formulatedat 2.5 and 5% as a cream that is typically used for the topicaltreatment of skin diseases. The selected concentrations of the2,5-dihydroxybenzene sulfonic acid salt is within the range of theconcentrations used for treatment of diabetic retinopathies: 6 tabletsper day of 500 mg of calcium salt of the 2,5-dihydroxybenzene sulfonicacid (Benakis A et al Thérapie 1974; 29: 211-219). Distilled water wasused as the aqueous phase of the cream. The fatty phase was by cetylicalcohol, stearic alcohol or Vaseline. The span is an emulsifierefficient in the preparation of the cream. Although both formulations(2.5 and 5%) of the product was shown to be clinically efficient, thebest therapeutic benefit was obtained at the concentration of 5%. Hencethe results herein are those obtained with the 2,5-dihydroxybenzenesulfonic acid formulated in the cream at 5%.

The following example illustrates one formulation of an efficient creamfor the topic treatment of psoriasis:

-   -   Active Component: (potassium salt of the 2,5-dihydroxybenzene        sulfonic acid at 5.6%)    -   Inactive Component: cetylic alcohol (2.5%), stearyl alcohol        (2.5%), liquid Vaseline (30%), white soft paraffin (20%),        sorbinate deato (5%) and distilled water (c.s.p. 100 g).

The clinical efficacy of the treatment was evaluated in accordance withthe index that quantifies the desquamation signs (D), erythema (E) andinfiltration (I) to which the following scoring system was assigned: (0)absent; (1) slight; (2) moderate and (3) severe (Freeman A K et al. J.Am. Acad Dermat 2003; 48: 564-568). FIG. 18 shows the images beforetreatment, six and eighteen days after treatment of the same chronicpsoriatic plaque located at the extension of the left elbow treated withthe potassium salt of the 2,5-dihydroxybenzene sulfonic acid at 5%. Aswas observed, the topical treatment two times at day with a creamcontaining the potassium salt of the 2,5-dihydroxybenzene sulfonic acidproduces an early (6 days) very notable “clearing” of the plaque withalmost total disappearance of hyperkeratosis. The therapeutic efficacyof the cream is more evident at the end of the second week of treatment(18 days). The treatment produces a significant reduction of the globalvalues of the DEI index (DEI global pre-treatment=6±1.57 vs. DEI globalpost-treatment=10.58; p<0.0001; unpaired student's t test).

The disclosure of each patent, patent application and publication citedor described in the present specification is hereby incorporated byreference herein in its entirety.

Although the invention has been set forth in detail, one skilled in theart will appreciate that numerous changes and modifications can be madeto the invention, and that such changes and modifications can be madewithout departing from the spirit and scope of the invention.

What is claimed is:
 1. A method for treating rosacea that is notcharacterized by papules and pustules in a patient having rosacea thatis not characterized by papules and pustules, comprising topicallyadministering to the patient a therapeutically effective amount ofpotassium 2,5-dihydroxybenzenesulfonate.
 2. The method of claim 1,further comprising administering a pharmaceutically acceptable carrier.3. The method of claim 1, further comprising at least one additionaltherapeutic agent.
 4. The method of claim 3, wherein the at least oneadditional therapeutic agent is selected from the group consisting of asteroid, a retinoid, an antimicrobial compound, an antioxidant, ananti-inflammatory compound, a vitamin D analogue and salicylic acid. 5.The method of claim 1, wherein the rosacea is characterized by erythema.6. A method for treating rosacea characterized by erythema in a patientin need thereof, comprising topically administering to a patient havingrosacea a therapeutically effective amount of a compound selected fromthe group consisting of: 2,5-dihydroxybenzene sulfonic acid; calcium2,5-dihydroxybenzenesulfonate; potassium 2,5-dihydroxybenzenesulfonate;magnesium 2,5-dihydroxybenzenesulfonate; and diethylamine2,5-dihydroxybenzenesulfonate.
 7. The method of claim 6, wherein therosacea is characterized by erythema in the absence of papules andpustules.
 8. The method of claim 6, further comprising administering apharmaceutically acceptable carrier.
 9. The method of claim 6, furthercomprising at least one additional therapeutic agent.
 10. The method ofclaim 9, wherein the at least one additional therapeutic agent isselected from the group consisting of a steroid, a retinoid, anantimicrobial compound, an antioxidant, an anti-inflammatory compound, avitamin D analogue and salicylic acid.
 11. A method for treating rosaceain a patient having rosacea, comprising topically administering to thepatient a composition comprising cetyl alcohol, stearyl alcohol, mineraloil, white petrolatum, and about 0.1% to about 15% (w/w) of a compoundselected from the group consisting of: 2,5-dihydroxybenzene sulfonicacid; calcium 2,5-dihydroxybenzenesulfonate; potassium2,5-dihydroxybenzenesulfonate, magnesium 2,5-dihydroxybenzenesulfonate;and diethylamine 2,5-dihydroxybenzenesulfonate.
 12. The method of claim1, wherein the potassium 2,5-dihydroxybenzene sulfonate is administeredin the form of a cream.
 13. The method of claim 1, wherein the potassium2,5-dihydroxybenzene sulfonate is administered in an amount from about0.1 to about 15% w/w.
 14. The method of claim 1, wherein the potassium2,5-dihydroxybenzene sulfonate is administered in an amount from about0.5 to about 10% w/w.
 15. The method of claim 1, wherein the potassium2,5-dihydroxybenzene sulfonate is administered in an amount from about 1to about 5% w/w.
 16. The method of claim 1, wherein the potassium2,5-dihydroxybenzene sulfonate is administered in an amount from about2.5 to about 4% w/w.
 17. The method of claim 1, wherein the potassium2,5-dihydroxybenzene sulfonate is administered once daily.
 18. Themethod of claim 1, wherein the potassium 2,5-dihydroxybenzene sulfonateis administered multiple times daily.
 19. The method of claim 1, whereinthe potassium 2,5-dihydroxybenzene sulfonate is administered for morethan one day.
 20. The method of claim 1, wherein the potassium2,5-dihydroxybenzene sulfonate is administered for more than one week.21. The method of claim 1, wherein the potassium 2,5-dihydroxybenzenesulfonate is administered for more than one month.